Abstract:
:A series of trivalent CD4-mimetic miniproteins was synthesized, in which three CD4M9 miniprotein moieties were tethered on a threefold-symmetric scaffold. The trivalent miniproteins were designed to target the CD4-binding sites displayed in the trimeric gp120 complex of HIV-1. The synthesis takes advantage of the highly efficient ligation between a cysteine-tagged CD4M9 miniprotein and a suitable trivalent maleimide that varied in the nature and length of spacer. Antiviral assay revealed that most of the synthetic trivalent miniproteins demonstrated significantly enhanced anti-HIV activities over the monomeric CD4M9 against both R5- and X4-tropic viruses, indicating the beneficial multivalent effects. One compound that possesses a hydrophobic linker was shown to be 140-fold more active than CD4M9 against HIV-1(Bal) infection, implicating a positive contribution of the lipid portion to the antiviral activity. It was also found that most of the trivalent miniproteins showed comparable anti-HIV activities in comparison with a typical bivalent miniprotein, regardless of the length of the linker. The results implicate a novel mechanism of the interactions between the multivalent inhibitors and the trimeric gp120 complex.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Li H,Guan Y,Szczepanska A,Moreno-Vargas AJ,Carmona AT,Robina I,Lewis GK,Wang LXdoi
10.1016/j.bmc.2007.03.064subject
Has Abstractpub_date
2007-06-15 00:00:00pages
4220-8issue
12eissn
0968-0896issn
1464-3391pii
S0968-0896(07)00260-Xjournal_volume
15pub_type
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